DNA vaccines have shown great promise in eliciting both humoral and cellular immune responses in a variety of rodent and non-human primate models. We are proposing to develop a DNA vaccine against schistosome infection which affects over 200 million people with an additional 600 million at risk in 74 countries. Our previous studies using the vaccine candidate Sm-p80 has shown that its efficacy can be improved by the addition of DNA encoding immunomodulatory cytokines (IL-2 and IL-12) in a DNA vaccine formulation. The experiments proposed in this application are designed to elucidate the mechanism(s) by which this important antigen confers immunity in an animal model system;this includes the role of different subsets of T cells and complement. The major objective of this proposal is to develop an effective protective vaccine against schistosomiasis. Second objective will be to examine the potential of a protective prophylactic vaccination strategy as a therapeutic treatment modality in an attempt to resolve a chronic parasitic infection and associated disease sequelae in mice and non-human primates. The development of schistosome-baboon chronic infection model may result in an important international resource for other investigations. The potential exists that the availability of such a well characterized animal model could provide insight and directly impact studies involving schistosome pathogenesis and transmission. It may also provide an invaluable research tool for future vaccine and therapeutic investigations. A schistosomiasis vaccine would make a great impact to existing means of disease control, especially if it provides an effective, long-term immunity against the infection. Parasitic disease, schistosomiasis continues to take an enormous toll on the human health in terms of both mortality and morbidity. This disease is endemic in 74 countries with 790 million people at risk. Schistosomes infect more than 200 million people with the highest prevalence and severity of infection occurring among school-age children. The sum of years of life lost through disability (DALYs) because of this debilitating and chronic disease has been estimated to be 1.7 million/year. In spite of advances in control via snail eradication and large-scale chemotherapy using praziquantel (a drug developed 30 years ago);this disease continues to spread to new geographic areas. Another alarming trend is the reported increase in resistance to praziquantel, the mainstay of current medical treatment. Presently, there is no vaccine for controlling this disease. Therefore a schistosomiasis vaccine would make a great impact on the existing means of disease control, especially if it provides an effective, long-term immunity against the infection. Based on published studies from our group for the past 17 years and recent preliminary data, we have identified a novel schistosome protein that was originally identified to be involved in the surface membrane biogenesis. This phenomenon has been considered to be one of the mechanisms utilized by blood-dwelling worms to evade the protective host immune response. This protein designated calpain, has two subunits, the larger of which, designated Sm-p80 has been demonstrated to be antigenic when administered to mice. Furthermore, immunization with various formulations of Sm-p80 has resulted in a significant level of protective immunity in mice following an experimental challenge with schistosome cercariae. We believe that Sm-p80 represents a unique target to invoke protective immunity against schistosome infection and, as such;a novel vaccine candidate. Based on promising results from our laboratory, the UNDP/World Bank/WHO-TDR special panel (Manila, Philippines, October 6-8, 2003), designated, Sm-p80 as one of the priority antigens with established credentials, needing further development and Sm-p80 is now considered as one of the first-tier candidates by international experts in the field. We are proposing to develop a Sm-p80-based schistosomiasis vaccine using a wide variety of approaches (e.g., naked DNA, prime-boost etc.). We intend to the test the prophylactic and therapeutic efficacy of this vaccine in animal models (mice and nonhuman primates). This vaccine can be administered to small children in order to prevent severe infection in the following years of high risk (3-12 years of age). This age group of children and young adolescents correspond to those ages in which contact with infected water is maximal. Booster doses of schistosomiasis vaccine may not be necessary since subsequent exposure to infective larvae could provide continuous re- stimulation to immunity. Such a vaccine would greatly reduce the need for logistically difficult and expensive drug-based programs and will save millions of lives.